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The mechanism by which bacterial toxins alter or interfere with secretion mechanisms are addressed in this chapter. After a brief description of the general mechanism of bacterial exotoxins, examples of key toxins affecting neurosecretion are commented upon. These comprise the botulinum and tetanus neurotoxins (BoNT and TeNT), which are toxins that divert synaptic vesicle (SV) recycling to enter nerve endings, and impair exocytosis by cleaving the soluble N-ethyl-maleimide-sensitive-factor attachment receptors (SNAREs). Given the important role of Rho, Rac, CDC42 GTPase, and F-actin in the vesicle/granule intracellular traffic and secretion processes, we address several examples of key bacterial cytotoxins affecting their cellular functions. We also briefly comment on the action of a few bacterial toxins that potentiate release of neurotransmitters.
Bernard Poulain; Frédéric Doussau. How Do Bacterial Neurotoxins Affect Neurosecretion? Neuroendocrine Clocks and Calendars 2020, 241 -269.
AMA StyleBernard Poulain, Frédéric Doussau. How Do Bacterial Neurotoxins Affect Neurosecretion? Neuroendocrine Clocks and Calendars. 2020; ():241-269.
Chicago/Turabian StyleBernard Poulain; Frédéric Doussau. 2020. "How Do Bacterial Neurotoxins Affect Neurosecretion?" Neuroendocrine Clocks and Calendars , no. : 241-269.
Bernard Poulain. Discussion suite à la communication : « Neurotoxine botulique : mécanismes moléculaires et cellulaires de son action sur le système nerveux ». Bulletin de l'Académie Nationale de Médecine 2020, 204, 393 -394.
AMA StyleBernard Poulain. Discussion suite à la communication : « Neurotoxine botulique : mécanismes moléculaires et cellulaires de son action sur le système nerveux ». Bulletin de l'Académie Nationale de Médecine. 2020; 204 (4):393-394.
Chicago/Turabian StyleBernard Poulain. 2020. "Discussion suite à la communication : « Neurotoxine botulique : mécanismes moléculaires et cellulaires de son action sur le système nerveux »." Bulletin de l'Académie Nationale de Médecine 204, no. 4: 393-394.
Les toxines botuliques sont des complexes de protéines formés d’une protéine neuro-active, la neurotoxine botulique (BoNT), et de protéines associées non toxiques. Toutes les indications médicales des toxines botuliques sont basées sur l’action inhibitrice de très longue durée de la BoNT sur la libération de neurotransmetteur. La BoNT est une protéine de 150 kDa qui se lie aux terminaisons nerveuses, est internalisée dans celles-ci et bloque la machinerie d’exocytose des neurotransmetteurs. Selon son sérotype la BoNT clive d’une des trois protéines SNARE impliquées dans la fusion des vésicules synaptiques avec la membrane plasmique des terminaisons nerveuses, indistinctement du type de transmetteur qu’elles contiennent. La très forte sélectivité d’action de la BoNT pour les terminaisons des neurones est principalement due à sa liaison à des récepteurs (synaptotagmine ou SV2 selon le sérotype de BoNT) qui sont des protéines des vésicules synaptiques exposées en surface des terminaisons des neurones à l’occasion de l’exocytose des neurotransmetteurs. La BoNT ne peut pas franchir la barrière hémato encéphalique. Ses effets sont majoritairement périphériques. Néanmoins, après une injection de BoNT en périphérie, une petite fraction de la neurotoxine capturée par les terminaisons nerveuses périphériques peut être transportée jusqu’aux corps cellulaires des neurones moteurs et sensitifs. La spécificité neuronale des BoNT en fait un outil thérapeutique utilisé dans de très nombreuses indications relevant de la médecine physique et de réadaptation, la neurologie, l'ophtalmologie, l'urologie et la prise en charge de la douleur. Botulinum toxins are protein complexes comprised of a neuroactive protein, botulinum neurotoxin (BoNT), and several non-toxic associated proteins. All medical indications for botulinum toxins are based on the very long-term inhibitory action of BoNT on the release of neurotransmitter. BoNT is a 150 kDa protein that binds to nerve endings, is internalized in them and blocks the vesicular neurotransmitter exocytosis machinery. Depending on its serotype, BoNT cleaves one among the three SNARE proteins involved in the fusion of synaptic vesicles with the plasma membrane of nerve endings, regardless of the type of transmitter they contain. The very high selectivity of action of BoNT for neuron nerve terminals is mainly due to its binding a protein receptor (synaptotagmin or SV2, depending on the BoNT serotype), which is a synaptic vesicle membrane protein exposed on the surface of neuron terminations during neurotransmitter exocytosis. BoNT cannot cross the blood-brain barrier, therefore, its effects are mainly peripheral. Nevertheless, after an injection of BoNT in the periphery, the neurotoxin captured by the peripheral nerve endings can be retrogradely transported inside sensory neurons where it can act, thereby modifying sensory information ascending to the central nervous system. The neuronal specificity of BoNT makes it a therapeutic tool used in a wide range of indications in physical and rehabilitation medicine, neurology, ophthalmology, urology and pain management.
Bernard Poulain; Michel R. Popoff. Neurotoxine botulique : mécanismes moléculaires et cellulaires de son action sur le système nerveux. Bulletin de l'Académie Nationale de Médecine 2020, 204, 369 -378.
AMA StyleBernard Poulain, Michel R. Popoff. Neurotoxine botulique : mécanismes moléculaires et cellulaires de son action sur le système nerveux. Bulletin de l'Académie Nationale de Médecine. 2020; 204 (4):369-378.
Chicago/Turabian StyleBernard Poulain; Michel R. Popoff. 2020. "Neurotoxine botulique : mécanismes moléculaires et cellulaires de son action sur le système nerveux." Bulletin de l'Académie Nationale de Médecine 204, no. 4: 369-378.
Epsilon toxin (ETX), produced by Clostridium perfringens types B and D, causes serious neurological disorders in animals. ETX can bind to the white matter of the brain and the oligodendrocytes, which are the cells forming the myelin sheath around neuron axons in the white matter of the central nervous system. After binding to oligodendrocytes, ETX causes demyelination in rat cerebellar slices. We further investigated the effects of ETX on cerebellar oligodendrocytes and found that ETX induced small transmembrane depolarization (by ~ +6.4 mV) in rat oligodendrocytes primary cultures. This was due to partial inhibition of the transmembrane inward rectifier potassium current (Kir). Of the two distinct types of Kir channel conductances (~25 pS and ~8.5 pS) recorded in rat oligodendrocytes, we found that ETX inhibited the large-conductance one. This inhibition did not require direct binding of ETX to a Kir channel. Most likely, the binding of ETX to its membrane receptor activates intracellular pathways that block the large conductance Kir channel activity in oligodendrocyte. Altogether, these findings and previous observations pinpoint oligodendrocytes as a major target for ETX. This supports the proposal that ETX might be a cause for Multiple Sclerosis, a disease characterized by myelin damage.
Jean Louis Bossu; Laetitia Wioland; Frédéric Doussau; Philippe Isope; Michel R. Popoff; Bernard Poulain. Epsilon Toxin from Clostridium perfringens Causes Inhibition of Potassium inward Rectifier (Kir) Channels in Oligodendrocytes. Toxins 2020, 12, 36 .
AMA StyleJean Louis Bossu, Laetitia Wioland, Frédéric Doussau, Philippe Isope, Michel R. Popoff, Bernard Poulain. Epsilon Toxin from Clostridium perfringens Causes Inhibition of Potassium inward Rectifier (Kir) Channels in Oligodendrocytes. Toxins. 2020; 12 (1):36.
Chicago/Turabian StyleJean Louis Bossu; Laetitia Wioland; Frédéric Doussau; Philippe Isope; Michel R. Popoff; Bernard Poulain. 2020. "Epsilon Toxin from Clostridium perfringens Causes Inhibition of Potassium inward Rectifier (Kir) Channels in Oligodendrocytes." Toxins 12, no. 1: 36.
Information processing by cerebellar molecular layer interneurons (MLIs) plays a crucial role in motor behavior. MLI recruitment is tightly controlled by the profile of short-term plasticity (STP) at granule cell (GC)-MLI synapses. While GCs are the most numerous neurons in the brain, STP diversity at GC-MLI synapses is poorly documented. Here, we studied how single MLIs are recruited by their distinct GC inputs during burst firing. Using slice recordings at individual GC-MLI synapses of mice, we revealed four classes of connections segregated by their STP profile. Each class differentially drives MLI recruitment. We show that GC synaptic diversity is underlain by heterogeneous expression of synapsin II, a key actor of STP and that GC terminals devoid of synapsin II are associated with slow MLI recruitment. Our study reveals that molecular, structural and functional diversity across GC terminals provides a mechanism to expand the coding range of MLIs.
Kevin Dorgans; Valérie Demais; Yannick Bailly; Bernard Poulain; Philippe Isope; Frédéric Doussau. Short-term plasticity at cerebellar granule cell to molecular layer interneuron synapses expands information processing. eLife 2019, 8, 1 .
AMA StyleKevin Dorgans, Valérie Demais, Yannick Bailly, Bernard Poulain, Philippe Isope, Frédéric Doussau. Short-term plasticity at cerebellar granule cell to molecular layer interneuron synapses expands information processing. eLife. 2019; 8 ():1.
Chicago/Turabian StyleKevin Dorgans; Valérie Demais; Yannick Bailly; Bernard Poulain; Philippe Isope; Frédéric Doussau. 2019. "Short-term plasticity at cerebellar granule cell to molecular layer interneuron synapses expands information processing." eLife 8, no. : 1.
Botulinum neurotoxins (BoNTs) are the most lethal toxins among all bacterial, animal, plant and chemical poisonous compounds. Although a great effort has been made to understand their mode of action, some questions are still open. Why, and for what benefit, have environmental bacteria that accidentally interact with their host engineered so diverse and so specific toxins targeting one of the most specialized physiological processes, the neuroexocytosis of higher organisms? The extreme potency of BoNT does not result from only one hyperactive step, but in contrast to other potent lethal toxins, from multi-step activity. The cumulative effects of the different steps, each having a limited effect, make BoNTs the most potent lethal toxins. This is a unique mode of evolution of a toxic compound, the high potency of which results from multiple steps driven by unknown selection pressure, targeting one of the most critical physiological process of higher organisms.
Bernard Poulain; Michel R. Popoff. Why Are Botulinum Neurotoxin-Producing Bacteria So Diverse and Botulinum Neurotoxins So Toxic? Toxins 2019, 11, 34 .
AMA StyleBernard Poulain, Michel R. Popoff. Why Are Botulinum Neurotoxin-Producing Bacteria So Diverse and Botulinum Neurotoxins So Toxic? Toxins. 2019; 11 (1):34.
Chicago/Turabian StyleBernard Poulain; Michel R. Popoff. 2019. "Why Are Botulinum Neurotoxin-Producing Bacteria So Diverse and Botulinum Neurotoxins So Toxic?" Toxins 11, no. 1: 34.
In the cerebellum, molecular layer interneurons (MLIs) play an essential role in motor behavior by exerting precise temporal control of Purkinje cells, the sole output of the cerebellar cortex. The recruitment of MLIs is tightly controlled by the release of glutamate from granule cells (GCs) during high-frequency activities. Here we study how single MLIs are recruited by their distinct unitary GC inputs during burst of GC stimulations. Stimulation of individual GC-MLI synapses revealed four classes of connections segregated by their profile of short-term plasticity. Each class of connection differentially drives MLI recruitment. Molecular and ultrastructural analyses revealed that GC-MLI synaptic diversity is underlain by heterogeneous expression of synapsin II at individual GC terminals. In synapsin II knock-out mice, the number of classes is reduced to profiles associated with slow MLI recruitment. Our study reveals that molecular diversity across GC terminals enables diversity in temporal coding by MLIs and thereby influences the processing of sensory information by cerebellar networks.
Kevin Dorgans; Valerie Demais; Yannick Bailly; Bernard Poulain; Philippe Isope; Frédéric Doussau. Molecular and functional heterogeneity of cerebellar granule cell terminals expands temporal coding in molecular layer interneurons. 2018, 338152 .
AMA StyleKevin Dorgans, Valerie Demais, Yannick Bailly, Bernard Poulain, Philippe Isope, Frédéric Doussau. Molecular and functional heterogeneity of cerebellar granule cell terminals expands temporal coding in molecular layer interneurons. . 2018; ():338152.
Chicago/Turabian StyleKevin Dorgans; Valerie Demais; Yannick Bailly; Bernard Poulain; Philippe Isope; Frédéric Doussau. 2018. "Molecular and functional heterogeneity of cerebellar granule cell terminals expands temporal coding in molecular layer interneurons." , no. : 338152.
The segregation of the readily releasable pool of synaptic vesicles (RRP) in sub-pools that are differentially poised for exocytosis shapes short-term plasticity. However, the frequency-dependent mobilization of these sub-pools is poorly understood. Using slice recordings and modeling of synaptic activity at cerebellar granule cell to Purkinje cell synapses of mice, we describe two sub-pools in the RRP that can be differentially recruited upon ultrafast changes in the stimulation frequency. We show that at low-frequency stimulations, a first sub-pool is gradually silenced, leading to full blockage of synaptic transmission. Conversely, a second pool of synaptic vesicles that cannot be released by a single stimulus is recruited within milliseconds by high-frequency stimulation and support an ultrafast recovery of neurotransmitter release after low-frequency depression. This frequency-dependent mobilization or silencing of sub-pools in the RRP in terminals of granule cells may play a role in the filtering of sensorimotor information in the cerebellum.
Frédéric Doussau; Hartmut Schmidt; Kevin Dorgans; Antoine M Valera; Bernard Poulain; Philippe Isope. Frequency-dependent mobilization of heterogeneous pools of synaptic vesicles shapes presynaptic plasticity. eLife 2017, 6, e28935 .
AMA StyleFrédéric Doussau, Hartmut Schmidt, Kevin Dorgans, Antoine M Valera, Bernard Poulain, Philippe Isope. Frequency-dependent mobilization of heterogeneous pools of synaptic vesicles shapes presynaptic plasticity. eLife. 2017; 6 ():e28935.
Chicago/Turabian StyleFrédéric Doussau; Hartmut Schmidt; Kevin Dorgans; Antoine M Valera; Bernard Poulain; Philippe Isope. 2017. "Frequency-dependent mobilization of heterogeneous pools of synaptic vesicles shapes presynaptic plasticity." eLife 6, no. : e28935.
Frédéric Doussau; Jean-Luc Dupont; Dorine Neel; Aline Schneider; Bernard Poulain; Jean Louis Bossu. Organotypic cultures of cerebellar slices as a model to investigate demyelinating disorders. Expert Opinion on Drug Discovery 2017, 12, 1011 -1022.
AMA StyleFrédéric Doussau, Jean-Luc Dupont, Dorine Neel, Aline Schneider, Bernard Poulain, Jean Louis Bossu. Organotypic cultures of cerebellar slices as a model to investigate demyelinating disorders. Expert Opinion on Drug Discovery. 2017; 12 (10):1011-1022.
Chicago/Turabian StyleFrédéric Doussau; Jean-Luc Dupont; Dorine Neel; Aline Schneider; Bernard Poulain; Jean Louis Bossu. 2017. "Organotypic cultures of cerebellar slices as a model to investigate demyelinating disorders." Expert Opinion on Drug Discovery 12, no. 10: 1011-1022.
The segregation of the readily releasable pool of synaptic vesicles (RRP) in sub-pool which are differentially poised for exocytosis shapes short-term plasticity at depressing synapses. Here, we used in vitro recording and modeling of synaptic activity at the facilitating mice cerebellar granule cell to Purkinje cell synapse to demonstrate the existence of two sub-pools of vesicles in the RRP that can be differentially recruited upon fast changes in the stimulation frequency. We show that upon low-frequency stimulation, a population of fully-releasable vesicles is silenced, leading to full blockage of synaptic transmission. A second population of vesicles, reluctant to release by simple stimuli, is recruited in a millisecond time scale by high-frequency stimulation to support an ultrafast recovery of neurotransmitter release after low-frequency depression. The frequency-dependent mobilization or silencing of sub-pools of vesicles in granule cell terminals should play a major role in the filtering of sensorimotor information in the cerebellum.
Frédéric Doussau; Hartmut Schmidt; Kevin Dorgans; Antoine M. Valera; Bernard Poulain; Philippe Isope. A frequency-dependent mobilization of heterogeneous pools of synaptic vesicles shapes presynaptic plasticity. 2017, 146753 .
AMA StyleFrédéric Doussau, Hartmut Schmidt, Kevin Dorgans, Antoine M. Valera, Bernard Poulain, Philippe Isope. A frequency-dependent mobilization of heterogeneous pools of synaptic vesicles shapes presynaptic plasticity. . 2017; ():146753.
Chicago/Turabian StyleFrédéric Doussau; Hartmut Schmidt; Kevin Dorgans; Antoine M. Valera; Bernard Poulain; Philippe Isope. 2017. "A frequency-dependent mobilization of heterogeneous pools of synaptic vesicles shapes presynaptic plasticity." , no. : 146753.
G. Zimmermann-Meisse; M.Y. Tawk; J.-L. Bossu; C. Potrich; T. Bourcier; M. Dalla Serra; B. Poulain; G. Prevost; E. Jover. The staphylococcal Panton and Valentine Leukocidin and γ-haemolysin HlgC/HlgB share C5aR as a receptor, but operate diverse intracellular activities in human polymorphonuclear neutrophils. Toxicon 2016, 116, 77 .
AMA StyleG. Zimmermann-Meisse, M.Y. Tawk, J.-L. Bossu, C. Potrich, T. Bourcier, M. Dalla Serra, B. Poulain, G. Prevost, E. Jover. The staphylococcal Panton and Valentine Leukocidin and γ-haemolysin HlgC/HlgB share C5aR as a receptor, but operate diverse intracellular activities in human polymorphonuclear neutrophils. Toxicon. 2016; 116 ():77.
Chicago/Turabian StyleG. Zimmermann-Meisse; M.Y. Tawk; J.-L. Bossu; C. Potrich; T. Bourcier; M. Dalla Serra; B. Poulain; G. Prevost; E. Jover. 2016. "The staphylococcal Panton and Valentine Leukocidin and γ-haemolysin HlgC/HlgB share C5aR as a receptor, but operate diverse intracellular activities in human polymorphonuclear neutrophils." Toxicon 116, no. : 77.
Michel R. Popoff; Bradley Stiles; Bernard Poulain. Clostridium perfringens Epsilon Toxin: Structural and Mechanistic Insights. Toxins and Drug Discovery 2016, 1 -20.
AMA StyleMichel R. Popoff, Bradley Stiles, Bernard Poulain. Clostridium perfringens Epsilon Toxin: Structural and Mechanistic Insights. Toxins and Drug Discovery. 2016; ():1-20.
Chicago/Turabian StyleMichel R. Popoff; Bradley Stiles; Bernard Poulain. 2016. "Clostridium perfringens Epsilon Toxin: Structural and Mechanistic Insights." Toxins and Drug Discovery , no. : 1-20.
A growing number of receptors, often associated with the innate immune response, are being identified as targets for bacterial toxins of the beta-stranded pore-forming family. These findings raise the new question of whether the receptors are activated or merely used as docking points facilitating the formation of a pore. To elucidate whether the Staphylococcus aureus Panton-Valentine leukocidin and the leukotoxin HlgC/HlgB act through the C5a receptor (C5aR) as agonists, antagonists or differ from the C5a complement-derived peptide, their activity is explored on C5aR-expressing cells. Both leukotoxins equally bound C5aR in neutrophils and in stable transfected U937 cells and initiated mobilization of intracellular Ca(2+) . HlgC/HlgB requires the presence of robust intracellular acidic Ca(2+) stores in order to evoke a rise in free [Ca(2+) ]i , while the LukS-PV/LukF-PV directly altered reticular Ca(2+) stores. Intracellular target specificity is conferred by the F-subunit associated to the S-subunit binding the receptor. Furthermore, internalization of the two leukotoxin components (S- and F-subunits) associated to C5aR is required for the initiation of [Ca(2+) ]i mobilization. Electrophysiological recordings on living cells demonstrated that LukS-PV/LukF-PV does not alter the membrane resistance of C5aR-expressing cells. The present observations suggest that part of the pore-forming process occurs in distinct intracellular compartments rather than at the plasma membrane.
Mira Y. Tawk; Gaëlle Zimmermann‐Meisse; Jean‐Louis Bossu; Cristina Potrich; Tristan Bourcier; Mauro Dalla Serra; Bernard Poulain; Gilles Prévost; Emmanuel Jover. Internalization of staphylococcal leukotoxins that bind and divert the C 5a receptor is required for intracellular Ca 2+ mobilization by human neutrophils. Cellular Microbiology 2015, 17, 1241 -1257.
AMA StyleMira Y. Tawk, Gaëlle Zimmermann‐Meisse, Jean‐Louis Bossu, Cristina Potrich, Tristan Bourcier, Mauro Dalla Serra, Bernard Poulain, Gilles Prévost, Emmanuel Jover. Internalization of staphylococcal leukotoxins that bind and divert the C 5a receptor is required for intracellular Ca 2+ mobilization by human neutrophils. Cellular Microbiology. 2015; 17 (8):1241-1257.
Chicago/Turabian StyleMira Y. Tawk; Gaëlle Zimmermann‐Meisse; Jean‐Louis Bossu; Cristina Potrich; Tristan Bourcier; Mauro Dalla Serra; Bernard Poulain; Gilles Prévost; Emmanuel Jover. 2015. "Internalization of staphylococcal leukotoxins that bind and divert the C 5a receptor is required for intracellular Ca 2+ mobilization by human neutrophils." Cellular Microbiology 17, no. 8: 1241-1257.
Epsilon toxin (ET) is produced by Clostridium perfringens types B and D and causes severe neurological disorders in animals. ET has been observed binding to white matter, suggesting that it may target oligodendrocytes. In primary cultures containing oligodendrocytes and astrocytes, we found that ET (10−9 M and 10−7 M) binds to oligodendrocytes, but not to astrocytes. ET induces an increase in extracellular glutamate, and produces oscillations of intracellular Ca2+ concentration in oligodendrocytes. These effects occurred without any change in the transmembrane resistance of oligodendrocytes, underlining that ET acts through a pore‐independent mechanism. Pharmacological investigations revealed that the Ca2+ oscillations are caused by the ET‐induced rise in extracellular glutamate concentration. Indeed, the blockade of metabotropic glutamate receptors type 1 (mGluR1) prevented ET‐induced Ca2+ signals. Activation of the N‐methyl‐D‐aspartate receptor (NMDA‐R) is also involved, but to a lesser extent. Oligodendrocytes are responsible for myelinating neuronal axons. Using organotypic cultures of cerebellar slices, we found that ET induced the demyelination of Purkinje cell axons within 24 h. As this effect was suppressed by antagonizing mGluR1 and NMDA‐R, demyelination is therefore caused by the initial ET‐induced rise in extracellular glutamate concentration. This study reveals the novel possibility that ET can act on oligodendrocytes, thereby causing demyelination. Moreover, it suggests that for certain cell types such as oligodendrocytes, ET can act without forming pores, namely through the activation of an undefined receptor‐mediated pathway.
Laetitia Wioland; Jean‐Luc Dupont; Frédéric Doussau; Stéphane Gaillard; Flavia Heid; Philippe Isope; Serge Pauillac; Michel R. Popoff; Jean‐Louis Bossu; Bernard Poulain. Epsilon toxin from C lostridium perfringens acts on oligodendrocytes without forming pores, and causes demyelination. Cellular Microbiology 2014, 17, 369 -388.
AMA StyleLaetitia Wioland, Jean‐Luc Dupont, Frédéric Doussau, Stéphane Gaillard, Flavia Heid, Philippe Isope, Serge Pauillac, Michel R. Popoff, Jean‐Louis Bossu, Bernard Poulain. Epsilon toxin from C lostridium perfringens acts on oligodendrocytes without forming pores, and causes demyelination. Cellular Microbiology. 2014; 17 (3):369-388.
Chicago/Turabian StyleLaetitia Wioland; Jean‐Luc Dupont; Frédéric Doussau; Stéphane Gaillard; Flavia Heid; Philippe Isope; Serge Pauillac; Michel R. Popoff; Jean‐Louis Bossu; Bernard Poulain. 2014. "Epsilon toxin from C lostridium perfringens acts on oligodendrocytes without forming pores, and causes demyelination." Cellular Microbiology 17, no. 3: 369-388.
Epsilon toxin (ET), produced by Clostridium perfringens types B and D, ranks among the four most potent poisonous substances known so far. ET-intoxication is responsible for enterotoxaemia in animals, mainly sheep and goats. This disease comprises several manifestations indicating the attack of the nervous system. This review aims to summarize the effects of ET on central nervous system. ET binds to endothelial cells of brain capillary vessels before passing through the blood-brain barrier. Therefore, it induces perivascular oedema and accumulates into brain. ET binding to different brain structures and to different component in the brain indicates regional susceptibility to the toxin. Histological examination has revealed nerve tissue and cellular lesions, which may be directly or indirectly caused by ET. The naturally occurring disease caused by ET-intoxication can be reproduced experimentally in rodents. In mice and rats, ET recognizes receptor at the surface of different neural cell types, including certain neurons (e.g. the granule cells in cerebellum) as well as oligodendrocytes, which are the glial cells responsible for the axons myelination. Moreover, ET induces release of glutamate and other transmitters, leading to firing of neural network. The precise mode of action of ET on neural cells remains to be determined.
Laetitia Wioland; Jean-Luc Dupont; Jean-Louis Bossu; Michel R. Popoff; Bernard Poulain. Attack of the nervous system by Clostridium perfringens Epsilon toxin: From disease to mode of action on neural cells. Toxicon 2013, 75, 122 -135.
AMA StyleLaetitia Wioland, Jean-Luc Dupont, Jean-Louis Bossu, Michel R. Popoff, Bernard Poulain. Attack of the nervous system by Clostridium perfringens Epsilon toxin: From disease to mode of action on neural cells. Toxicon. 2013; 75 ():122-135.
Chicago/Turabian StyleLaetitia Wioland; Jean-Luc Dupont; Jean-Louis Bossu; Michel R. Popoff; Bernard Poulain. 2013. "Attack of the nervous system by Clostridium perfringens Epsilon toxin: From disease to mode of action on neural cells." Toxicon 75, no. : 122-135.
Botulism and tetanus are two severe neurological diseases in man and animals. While botulism is characterized by a descendant flaccid paralysis, tetanus consists in spastic paralysis. In the severe forms of both diseases, death occurs by respiratory distress. Botulism and tetanus are caused by neurotoxins, botulinum neurotoxin (BoNT), and tetanus toxin (TeNT), respectively, which are produced by anaerobic sporulating bacteria, Clostridium botulinum and Clostridium tetani, respectively. In contrast to C. tetani, which forms a homogeneous bacterial species, BoNT-producing Clostridia are divided into several bacterial species and groups. These Clostridia are widely distributed in the environment, including food notably for C. botulinum, where they can survive during long periods in the sporulating forms. BoNTs and TeNT share a common structural organization consisting in a light (L) chain (about 50 kDa) linked by a disulfide bridge to the heavy (H) chain (about 100 kDa). Only a unique TeNT is known, while BoNTs encompass seven toxinotypes (A to G, BoNT/A, B, and E mainly involved in human botulism, and BoNT/C and D mainly responsible for animal botulism), which are subdivided into several subtypes according to amino acid sequence variations. H chain, which contains a C-terminal receptor-binding domain and an N-terminal translocation domain, delivers the L chain into target neurons. BoNTs target the motoneuron endings or neuromuscular junctions, and TeNT is transported to central inhibitory interneurons through a retrograde axonal pathway along motoneurons. Both BoNT and TeNT block the release of neurotransmitter by an L chain-mediated proteolytic cleavage of SNARE proteins (synaptobrevin, SNAP25, or syntaxin) which are involved in the neuroexocytosis process. Blockage of acetylcholine release at the neuromuscular junctions by BoNTs induces a flaccid paralysis, whereas TeNT-dependent inhibition of glycine or GABA exocytosis in inhibitory interneurons results in spastic paralysis. Botulism is mainly acquired by ingestion of preformed BoNT in food, but it may also occur subsequently to intestinal or wound colonization by C. botulinum. Tetanus essentially results from a wound contamination by C. tetani. BoNT/A is the most potent toxin with a long activity duration in neurons, and it is also a therapeutic agent widely used to treat hypercholinergic diseases including localized muscle spasticity, dystonia, autonomic dysfunctions (hyperhidrosis, hypersalivation), and also pain such as migraine headaches.
Michel R. Popoff; Christelle Mazuet; B. Poulain. Botulism and Tetanus. The Prokaryotes 2013, 247 -290.
AMA StyleMichel R. Popoff, Christelle Mazuet, B. Poulain. Botulism and Tetanus. The Prokaryotes. 2013; ():247-290.
Chicago/Turabian StyleMichel R. Popoff; Christelle Mazuet; B. Poulain. 2013. "Botulism and Tetanus." The Prokaryotes , no. : 247-290.
Repetitive firing of neurons at a low frequency often leads to a decrease in synaptic strength. The mechanism of this low-frequency depression (LFD) is poorly understood. Here, LFD was studied at Aplysia cholinergic synapses. The absence of a significant change in the paired-pulse ratio during LFD, together with the facts that neither the time course nor the extent of LFD were affected by the initial release probability, suggests that LFD is not related to a depletion of the ready-to-fuse synaptic vesicles (SVs) or to a decrease in the release probability, but results from the silencing of a subpopulation of release sites. A subset of SVs or release sites, which acquired a high release probability status during LFD, permits synapses to rapidly and temporarily recover the initial synaptic strength when the stimulation is stopped. However, the recovery of the full capacity of the synapse to sustain repetitive stimulations is slow and involves spontaneous reactivation of the silent release sites. Application of tetanic stimulations accelerates this recovery by immediately switching on the silent sites. This high-frequency-dependent phenomenon underlies a new form of synaptic plasticity that allows resetting of presynaptic efficiency independently of the recent history of the synapse. Microinjection of a mutated Aplysia synapsin that cannot be phosphorylated by cAMP-dependent protein kinase (PKA), or a PKA inhibitor both prevented high-frequency-dependent awakening of release sites. Changes in the firing pattern of neurons appear to be able to regulate the on–off status of release sites via a molecular cascade involving PKA-dependent phosphorylation of synapsin.
Frédéric Doussau; Yann Humeau; Fabio Benfenati; Bernard Poulain. A Novel Form of Presynaptic Plasticity Based on the Fast Reactivation of Release Sites Switched Off during Low-Frequency Depression. The Journal of Neuroscience 2010, 30, 16679 -16691.
AMA StyleFrédéric Doussau, Yann Humeau, Fabio Benfenati, Bernard Poulain. A Novel Form of Presynaptic Plasticity Based on the Fast Reactivation of Release Sites Switched Off during Low-Frequency Depression. The Journal of Neuroscience. 2010; 30 (49):16679-16691.
Chicago/Turabian StyleFrédéric Doussau; Yann Humeau; Fabio Benfenati; Bernard Poulain. 2010. "A Novel Form of Presynaptic Plasticity Based on the Fast Reactivation of Release Sites Switched Off during Low-Frequency Depression." The Journal of Neuroscience 30, no. 49: 16679-16691.
Epsilon toxin (ET) produced by C. perfringens types B and D is a highly potent pore-forming toxin. ET-intoxicated animals express severe neurological disorders that are thought to result from the formation of vasogenic brain edemas and indirect neuronal excitotoxicity. The cerebellum is a predilection site for ET damage. ET has been proposed to bind to glial cells such as astrocytes and oligodendrocytes. However, the possibility that ET binds and attacks the neurons remains an open question. Using specific anti-ET mouse polyclonal antibodies and mouse brain slices preincubated with ET, we found that several brain structures were labeled, the cerebellum being a prominent one. In cerebellar slices, we analyzed the co-staining of ET with specific cell markers, and found that ET binds to the cell body of granule cells, oligodendrocytes, but not astrocytes or nerve endings. Identification of granule cells as neuronal ET targets was confirmed by the observation that ET induced intracellular Ca2+ rises and glutamate release in primary cultures of granule cells. In cultured cerebellar slices, whole cell patch-clamp recordings of synaptic currents in Purkinje cells revealed that ET greatly stimulates both spontaneous excitatory and inhibitory activities. However, pharmacological dissection of these effects indicated that they were only a result of an increased granule cell firing activity and did not involve a direct action of the toxin on glutamatergic nerve terminals or inhibitory interneurons. Patch-clamp recordings of granule cell somata showed that ET causes a decrease in neuronal membrane resistance associated with pore-opening and depolarization of the neuronal membrane, which subsequently lead to the firing of the neuronal network and stimulation of glutamate release. This work demonstrates that a subset of neurons can be directly targeted by ET, suggesting that part of ET-induced neuronal damage observed in neuronal tissue is due to a direct effect of ET on neurons.
Etienne Lonchamp; Jean-Luc Dupont; Laetitia Wioland; Raphaël Courjaret; Corinne Mbebi-Liegeois; Emmanuel Jover; Frédéric Doussau; Michel R. Popoff; Jean-Louis Bossu; Jean De Barry; Bernard Poulain. Clostridium perfringens Epsilon Toxin Targets Granule Cells in the Mouse Cerebellum and Stimulates Glutamate Release. PLOS ONE 2010, 5, e13046 .
AMA StyleEtienne Lonchamp, Jean-Luc Dupont, Laetitia Wioland, Raphaël Courjaret, Corinne Mbebi-Liegeois, Emmanuel Jover, Frédéric Doussau, Michel R. Popoff, Jean-Louis Bossu, Jean De Barry, Bernard Poulain. Clostridium perfringens Epsilon Toxin Targets Granule Cells in the Mouse Cerebellum and Stimulates Glutamate Release. PLOS ONE. 2010; 5 (9):e13046.
Chicago/Turabian StyleEtienne Lonchamp; Jean-Luc Dupont; Laetitia Wioland; Raphaël Courjaret; Corinne Mbebi-Liegeois; Emmanuel Jover; Frédéric Doussau; Michel R. Popoff; Jean-Louis Bossu; Jean De Barry; Bernard Poulain. 2010. "Clostridium perfringens Epsilon Toxin Targets Granule Cells in the Mouse Cerebellum and Stimulates Glutamate Release." PLOS ONE 5, no. 9: e13046.
Toxins are potent molecules used by various bacteria to interact with a host organism. Some of them specifically act on neuronal cells (clostridial neurotoxins) leading to characteristics neurological affections. But many other toxins are multifunctional and recognize a wider range of cell types including neuronal cells. Various enterotoxins interact with the enteric nervous system, for example by stimulating afferent neurons or inducing neurotransmitter release from enterochromaffin cells which result either in vomiting, in amplification of the diarrhea, or in intestinal inflammation process. Other toxins can pass the blood brain barrier and directly act on specific neurons.
Michel R. Popoff; Bernard Poulain. Bacterial Toxins and the Nervous System: Neurotoxins and Multipotential Toxins Interacting with Neuronal Cells. Toxins 2010, 2, 683 -737.
AMA StyleMichel R. Popoff, Bernard Poulain. Bacterial Toxins and the Nervous System: Neurotoxins and Multipotential Toxins Interacting with Neuronal Cells. Toxins. 2010; 2 (4):683-737.
Chicago/Turabian StyleMichel R. Popoff; Bernard Poulain. 2010. "Bacterial Toxins and the Nervous System: Neurotoxins and Multipotential Toxins Interacting with Neuronal Cells." Toxins 2, no. 4: 683-737.
Botulinum toxin is a multi-molecular complex comprised of a neuro-active moiety (i.e. botulinum neurotoxin) and several associated non-toxic proteins. The toxin dissociates rapidly at plasmatic pH, thereby releasing neurotoxin. Nerve terminals only take up the neurotoxin. In the peripheral nerve system, the neurotoxin mainly blocks acetylcholine release. When acting at the neuromuscular junctions, this results in paralysis of the muscle fibers. The duration of the neurotoxin action is mainly determined by the life-time of neurotoxin molecules inside the nerve terminals. Inhibition of cholinergic transmission induces rapid atrophy of the muscle fibres, and, sometimes, sprouting from poisoned nerve terminals. These effects, as well as the acetylcholine release blockade are entirely reversible. When injected in the periphery, a direct action of botulinum neurotoxin in the central nervous system remains unlikely despite its retrograde ascent demonstrated in animal models. However, indirect effects are numerous. The constituting proteins of the toxin complex can lead to immunisation against the non-toxic associated proteins and neurotoxin. Only the antibodies directed against neurotoxin are potentially neutralizing.
B. Poulain. La neurotoxine botulinique. Revue Neurologique 2010, 166, 7 -20.
AMA StyleB. Poulain. La neurotoxine botulinique. Revue Neurologique. 2010; 166 (1):7-20.
Chicago/Turabian StyleB. Poulain. 2010. "La neurotoxine botulinique." Revue Neurologique 166, no. 1: 7-20.